Comparative in Vitro Activities of Cefpiramide and Apalcillin Individually and in Combination J

Home , Cefpiramide, Cefsulodin

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 1985, p. 782-790 Vol. 27, No. 5 0066-4804/85/050782-09$02.00/0 Copyright X 1985, American Society for Microbiology Comparative In Vitro Activities of Cefpiramide and Apalcillin Individually and in Combination J. DAVIS ALLAN,'2 GEORGE M. ELIOPOULOS,1.2* MARY JANE FERRARO,2'3 AND ROBERT C. MOELLERING, JR."12 Department of Medicine, New England Deaconess Hospital, Boston, Massachusetts 022151*; Francis Blake Bacteriology Laboratories, Massachusetts General Hospital, Boston, Massachusetts 021143; and Harvard Medical School, Boston, Massachusetts 021152 Received 2 November 1984/Accepted 18 February 1985

The in vitro activities of cefpiramide and apalcillin were compared with those of other third-generation cephalosporins and extended-spectrum penicillins against over 1,000 clinical bacterial isolates. The activity of cefpiramide against Pseudomonas aeruginosa was comparable to those of piperacillin and cefoperazone, inhibiting 90% of strains at concentrations sl6.0 ,ug/ml. This drug was also active against a broad range of gram-negative organisms but was generally less active than many of the other cephalosporins tested against members of the family Enterobacteriaceae. The activity of cefpiramide against gram-positive organisms was comparable to that of cefoperazone. Apalcillin, along with ceftazidime, was the most active agent tested against P. aeruginosa and Acinetobacter calcoaceticus subsp. anitratus, inhibiting 90% of these strains at concentrations <8 ,Lg/ml. Against other gram-negative and gram-positive organisms, its activity was similar to that of piperacillin. The activities of both cefpiramide and apalcillin were significantly reduced by the presence of several plasmid-mediated j-lactamases in a series of otherwise isogenic strains of P. aeruginosa in comparison with their activities against a parent strain which lacks these enzymes. Many strains of Enterobacter cloacae were synergistically inhibited by the combination of gentamicin with either cefpiramide (5 of 10 strains) or apalcillin (6 of 10 strains). Most strains of P. aeruginosa were synergistically inhibited by the combination of gentamicin with either cefpiramide (8 of 10 strains) or apalcillin (10 of 10 strains). However, cefoxitin antagonized the activity of both cefpiramide and apalcillin against most of these same strains.

Cefpiramide (SM-1652, WY-44,635) is a new semisyn- MATERIALS AND METHODS thetic cephalosporin that is structurally related to cefoperazone. A number of recent studies have documented its Bacterial strains. Gram-negative bacteria used in this study broad spectrum of activity against both gram-negative and were routine clinical isolates recently collected (1983 to 1984) gram-positive organisms. Compared with other cephalospo- from the New England Deaconess Hospital and the Massa- rins, it is particularly active against Pseudomonas aerugi- chusetts General Hospital, Boston. The organisms collected nosa (6, 8, 14). In addition, cefpiramide has a half-life of were isolated from multiple body sites including urine, spu- approximately 4.5 h in humans, which is significantly longer tum, blood, feces, wounds, and cerebrospinal fluid. Dupli- than those of other third-generation cephalosporins, such as cate isolates from individual patients were excluded, but ceftazidime and cefoperazone, but shorter than that of otherwise isolates were unselected. P-Lactamase-producing ceftriaxone (10). strains of Neisseria gonorrhoeae were kindly provided by Apalcillin (PC-904) is a naphthyridine derivative of ampi- Clyde Thornsberry (Centers for Disease Control, Atlanta, cillin. Its spectrum of activity is similar to that of piperacil- Ga.). lin, although it exhibits greater activity against P. aerugi- Routine gram-positive isolates had been collected earlier nosa than does piperacillin (1, 5, 12, 13). Apalcillin also at the Massachusetts General Hospital. Penicillin-resistant differs from piperacillin in having a slightly longer half-life pneumococci and viridans group streptococci were obtained and in being largely eliminated by hepatobiliary mechanisms as previously reported (3, 4). In certain specified studies, (9). multiply resistant gram-negative bacilli were used from our In the present study, we examined the in vitro activity of collection established over the past 5 to 10 years. The both cefpiramide and apalcillin against more than 1,000 following MIC criteria were used for defining resistance: routine clinical isolates of gram-positive and gram-negative amikacin, .32 ,ug/ml; gentamicin, .8 ,ug/ml; carbenicillin, bacteria as well as organisms selected for resistance to .32 ,ug/ml (.250 ,ug/ml for P. aeruginosa); cephalothin, .32 multiple antibiotics. The activity of these two agents was p,g/ml; cefamandole, .32 ,ug/ml; and cefoxitin, .32 ,ug/ml also tested in combination with other P-lactams and gen- (11). P. aeruginosa transconjugants containing various de- tamicin. fined plasmid-mediated P-lactamases were provided by was presented in part at the 24th Interscience George Jacoby (Massachusetts General Hospital) and have (This work been described previously (2). Conference on Antimicrobial Agents and Chemotherapy reference [J. D. Allan, G. M. Eliopoulos, and R. C. Moellering, Jr., Antimicrobial agents. Standard antimicrobial Program Abstr. 24th Intersci. Conf. Antimicrob. Agents powders were obtained from the following sources: apalcil- abstr. no. 650, 1984].) lin and cefpiramide, Wyeth Laboratories, Inc., Philadelphia, Chemother., Pa.; piperacillin, Lederle Laboratories, Pearl River, N.Y.; moxalactam, cefamandole, and cephalothin, Eli Lilly & Co., Indianapolis, Ind.; imipenem and cefoxitin, Merck Sharp & * Corresponding author. Dohme, Rahway, N.J.; aztreonam, E. R. Squibb & Sons, 782 VOL. 27, 1985 IN VITRO ACTIVITIES OF CEFPIRAMIDE AND APALCILLIN 783

TABLE 1. Comparative in vitro activities of cefpiramide and apalcillin Organism (no. of isolates) Antibiotic MIC(ILg/ml)range (,ug/ml)MIC50 (jig/ml)MICgo Pseudomonas aeruginosa (90) Cefpiramide 0.25->128 4 16 Apalcillin <0.06->128 2 8 Piperacillin 0.5->128 8 16 Azlocillin 1.0->128 16 32 Aztreonam 0.25-128 8 32 Cefoperazone 2.0->128 8 32 Ceftriaxone 8.0->128 64 >128 Ceftazidime 1.0->128 2 8 Cefsulodin 1.0-128 8 32 Gentamicin 0.5->128 4 8 Pseudomonas cepacia (10) Cefpiramide 1.0-> 128 65 >128 Apalcillin 1.0->128 16 >128 Piperacillin 0.5->128 32 >128 Aztreonam 2.0->128 64 >128 Cefoperazone 8.0->128 128 >128 Ceftriaxone 0.5-32 0.5 16 Ceftazidime 0.5-16 2 16 Gentamicin 1.0->128 32 >128 Pseudomonas fluorescenslputida Cefpiramide 8.0-32 16 16 (10) Apalcillin 2.0-8 4 4 Piperacillin 2.0-32 8 16 Aztreonam 32.0-128 64 >128 Cefoperazone 8.0-64 8 16 Ceftriaxone 16.0-128 16 128 Ceftazidime 1.0-16 2 16 Gentamicin .0.06->128 0.25 1 Pseudomonas maltophilia (20) Cefpiramide 2.0-128 32 64 Apalcillin 2.0->128 32 128 Piperacillin 32.0->128 128 >128 Aztreonam 8.0->128 128 >128 Cefoperazone 8.0->128 32 64 Ceftriaxone 32.0->128 >128 >128 Ceftazidime 2.0->128 8 128 Gentamicin 1.0->128 32 >128 Acinetobacter calcoaceticus subsp. Cefpiramide 4.0-128 32 64 antiratus (30) Apalcillin 4.0-16 8 8 Piperacillin 2.0->128 16 32 Aztreonam 8.0->128 32 64 Cefoperazone 16.0->128 64 >128 Ceftriaxone 2.0-64 16 16 Ceftazidime 4.0-32 4 8 Gentamicin 0.25-64 1 2 Aeromonas hydrophila (10) Cefpiramide 1.0-32 2 8 Apalcillin 2.0-128 4 8 Piperacillin 1.0-128 2 4 Aztreonam s0.06-0.25 S0.06 .0.06 Cefoperazone 0.25-8 0.5 2 Ceftriaxone .0.06-4 0.5 4 Ceftazidime 0.125-2 0.25 1 Gentamicin 0.25-2 0.25 1 Haemophilus influenzae (1- Cefpiramide .0.06-0.5 0.125 0.250 lactamase negative) (20) Apalcillin .0.06-2 0.25 0.5 Piperacillin .0.06-0.5 S0.06 0.125 Aztreonam .0.06-0.25 S0.06 .0.06 Cefoperazone .0.06-0.125 S0.06 .0.06 Ceftriaxone <0.06 S0.06 .0.06 Ceftazidime 50.06-0.5 0.125 0.125 Gentamicin 0.25-8 2 4 Haemophilus influenzae (1- Cefpiramide 1.0-4 2 2 lactamase positive) (10) Apalcillin 128.0->128 >128 >128 Piperacillin 32.0->128 128 >128 Continued on following page 784 ALLAN ET AL. ANTIMICROB. AGENTS CHEMOTHER.

TABLE 1-Continued Organism (no. of isolates) MIC range MIC50 MICgo Antibiotic (,ug/ml) (>g/m1) (,Lg/ml) Aztreonam '0.06 <0.06 .0.06 Cefoperazone 0.125-0.5 0.125 0.5 Ceftriaxone '0.06 <0.06 .0.06 Ceftazidime '0.06-0.125 0.125 0.125 Gentamicin 2.0-4 2 4 Neisseria gonorrhoeae (P- Cefpiramide '0.06-0.25 <0.06 0.125 lactamase negative) (10) Apalcillin '0.06-0.5 <0.06 0.25 Piperacillin '0.06-0.5 '0.06 .0.06 Aztreonam '0.06-0.125 <0.06 .0.06 Cefoperazone '0.06-0.25 <0.06 .0.06 Ceftriaxone s0.06 <0.06 .0.06 Ceftazidime '0.06-0.25 <0.06 .0.06 Penicillin '0.06-0.125 <0.06 .0.06 Neisseria gonorrhoeae (1- Cefpiramide '0.06-0.5 0.25 0.5 lactamase positive) (8) Apalcillin 1.0-32 2 16 Piperacillin 0.5-32 1 8 Aztreonam s0.06-0.125 <0.06 .0.06 Cefoperazone '0.06-0.25 0.125 0.25 Ceftriaxone '0.06 <0.06 .0.06 Ceftazidime '0.06 <0.06 s0.06 Penicillin 1.0-64 8 64 Pasteurella multocida (10) Cefpiramide '0.06-0.125 <0.06 0.125 Apalcillin '0.06 <0.06 .0.06 Piperacillin '0.06-0.125 <0.06 0.125 Aztreonam s0.06 <0.06 .0.06 Cefoperazone .0.06 <0.06 0.125 Ceftriaxone '0.06 <0.06 .0.06 Ceftazidime '0.06-0.25 0.125 0.25 Gentamicin 0.125-1 1 1 Citrobacter diversus (10) Cefpiramide 0.125-2 0.5 2 Apalcillin 1.0-8 4 8 Piperacillin 1.0-8 4 8 Aztreonam .0.06 .0.06 .0.06 Cefoperazone '0.06-0.25 .0.06 0.125 Ceftriaxone .0.06-0.25 .0.06 .0.06 Ceftazidime '0.06-0.125 '0.06 .0.06 Gentamicin .0.06-1.0 0.25 0.5 Citrobacterfreundii (40) Cefpiramide 1.0->128 4 >128 Apalcillin 1.0->128 2 >128 Piperacillin 1.0->128 4 128 Aztreonam .0.06-64 0.125 32 Cefoperazone 0.125->128 0.5 128 Ceftriaxone .0.06-128 0.125 64 Ceftazidime 0.125->128 0.5 128 Gentamicin 0.25-64 0.5 1 Escherichia coli (90) Cefpiramide 0.125->128 1 32 Apalcillin 0.5->128 1 128 Piperacillin 0.5->128 2 128 Aztreonam s0.06-0.25 .0.06 0.125 Cefoperazone .0.06-32 0.25 4 Ceftriaxone .0.06 .0.06 .0.06 Ceftazidime s0.06-0.5 0.125 0.25 Gentamicin 0.25-2 0.5 1

Enterobacter spp. (90) Cefpiramide 0.25->128 4 128 Apalcillin 0.5->128 4 64 Piperacillin 0.25->128 4 32 Aztreonam .0.06-64 .0.06 16 Cefoperazone s0.06->128 0.5 16 Ceftriaxone s0.06->128 0.125 16 Ceftazidime s0.06-128 0.25 32 Gentamicin 0.25-1 0.5 0.5 Continued on following page VOL. 27, 1985 IN VITRO ACTIVITIES OF CEFPIRAMIDE AND APALCILLIN 785

TABLE 1-Continued

(Kog/ml)Organism (no. of isolates) Antibiotic(rg/ml)MIC range (,g/ml)MIC50 MICgo klebsie'lla oxytoca (30) Cefpiramide 1.0->128 8 32 Apalcillin 4.0->128 8 16 Piperacillin 1.0->128 8 32 Aztreonam .0.06-2 .0.06 0.5 Cefoperazone 0.125->128 2 4 Ceftriaxone 0.06-0.5 .0.06 0.125 Ceftazidime ..O06-0.5 0.125 0.125 Gentamicin 0.25-1 0.5 0.5 Klebsiella pneumoniae (60) Cefpirainide 0.125-64 2 16 Apalcillin 0.5-64 8 16 Piperacillin 1.0-64 4 32 Aztreonam <0.06-0.5 s0.06 s0.06 Cefoperazone <0.06-8 0.25 i Ceftriaxone s0.06-.0.5 s0.06 0.125 Ceftazidime s0.06-4 0.25 4 Gentamicin 0.25-8 0.5 1 Morganella morganii (30) Cefpiramide 8.0-s128 16 32 Apalcillin 2.0-s128 2 32 Piperacillin 0.5-64 1 8 Aztreonam s0.06-1 s0.06 .0.06 Cefoperazone 0.5-32 1 4 Ceftriaxone s0.06-i s0.06 0.125 Ceftazidime <0.06-16 .0.06 0.5 Gentamicin 0.25-1 0.25 0.5 Proteus mirabilis (70) Cefpiramide 1.0-128 8 8 Apalcillin 0.25->128 2 2 Piperacillin 0.25->128 0.5 1 Aztreonam s0.06-0.125 .0.06 s0.06 Cefoperazone 0.25-8 1 2 Ceftriaxone s0.06-0.25 .0.06 .0.06 Ceftazidime s0.06-2 s0.06 .0.06 Gentamicin 0.125-8 1 2 Proteus vulgaris (20) Cefpiramide 4.0-32 8 32 Apalcillin 1.0-8 4 4 Piperacillin 0.5-8 2 4 Aztreonam s0.06 .0.06 50.06 Cefoperazone 0.5-8 2 4 Ceftriaxone 50.06-1 0.25 0.5 Ceftazidime .0.06-0.25 .0.06 0.125 Gentamicin 0.25-8 1 4 Providencia spp. (16) Cefpiramide 4.0-128 4 128 Apalcillin 1.0->128 2 >128 Piperacillin 0.5->128 1 >128 Aztreonam 50.06 .0.06 s0.06 Cefoperazone 0.25-32 1 16 Ceftriaxone .0.06-0.125 s0.06 .0.06 Ceftazidime s0.06-2 0.125 1 Gentamicin 0.125-32 0.5 16 Serratia marcescens (60) Cefpiramide 8.0->128 64 >128 Apalci!lin 1.0->128 32 128 Piperacillin 1.0->128 8 64 Aztreonam 0.06->128 0.25 1 Cefoperazone 1.0->128 4 32 Ceftriaxone .0.06->128 0.5 8 Ceftazidime 0.125->128 0.25 2 Gentamicin 0.5-64 1 32 Salmonella enteritidis (10) Cefpiramide 4.0->128 4 8 Apalcillin 2.0->128 2 8 Piperacillin 2.0->128 2 8 Aztreonam .0.06-0.25 .0.06 0.125 Cefoperazone 0.5-32 0.5 2 Continued on following page 786 ALLAN ET AL. ANTIMICROB. AGENTS CHEMOTHER.

TABLE 1-Continued Antibiotic MIC range MIC90 Organism (no. of isolates) (pg/ml) (,ug/ml)MIC50 (pg/mi) Ceftriaxone s0.06-0.25 s0.06 0.125 Ceftazidime 0.25-1 0.5 0.5 Gentamicin 0.25-1 0.5 1 Staphylococcus aureus (methicillin Cefpiramide 2.0-4 2 4 susceptible) (30) Apalcillin 2.0-128 8 64 Piperacillin 1.0-128 16 128 Aztreonam >128 >128 >128 Cefoperazope 2.0-8 4 8 Ceftriaxone 2.0-4 4 4 Ceftazidime 8.0-32 16 16 Gentamicin 0.25-32 0.5 0.05 Staphylococcus aureus (methicillin Cefpiramide 16-128 64 128 resistant) (20) Apalcillin 64->128 128 >128 Piperacillin 128->128 >128 >128 Aztreonam >128 >128 >128 Cefoperazone 32->128 128 >128 Ceftriaxone 32-> 128 >128 >128 Ceftazidime 128->128 >128 >128 Gentamicin 0.25-128 64 64 Staphylococcus epidermidis (30) Cefpiramide 0.25-8 2 8 Apalcillin s0.06-64 2 32 Piperacillin s0.06-64 2 64 Aztreonam 128->128 >128 >128 Cefoperazone 0.5-8 2 8 Ceftriaxone 0.5->128 4 64 Ceftazidime 2.0-64 8 64 Gentamicin 0.06-128 0.125 32 Streptococcus faecalis (30) Cefpiramide 8.0-32 16 32 Apalcillin 2.0-8 4 4 Piperacillin 2.0-8 4 4 Aztreonam >128 >128 >128 Cefoperazone 16-64 32 64 Ceftriaxone 128->128 >128 >128 Ceftazidime >128 >128 >128 Gentamicin 8.0->128 16 32 Streptococcus pyogenes (10) Cefpiramide <0.06-0.125 0.125 0.125 Apalcillin 0.06-0.125 0.125 0.125 Piperacillin s0.06-0.25 0.125 0.125 Aztreonam 8.0-16 16 16 Cefoperazone 0.125-0.25 0.125 0.25 Ceftriaxone <0.06 <0.06 o0.06 Ceftazidime sQ.06-0.25 0.125 0.125 Gentamicin 1.0-8 4 8 Streptococcus agalactiae (10) Cefpiramide 0.25-2 0.5 0.5 Apalcillin 0.25-2 0.5 0.5 Piperacillin 0.25-2 0.25 0.5 Aztreonam 128->128 >128 >128 Cefoperazone 0.125-2 0.25 0.25 Ceftriaxone s0.06-0.25 <0.06 C0.06 Ceftazidime 0.5-2 0.5 0.5 Gentamicin 16-64 16 32 Streptococcus pneumoniae Cefpiramide 0.25-8 1 8 (penicillin resistant) (9) Apalcillin 0.125-8 2 8 Piperacillin 0.25-16 4 16 Aztreonam 64->128 >128 >128 Cefoperazone 0.5-8 2 8 Ceftriaxone 0.125-4 1 4 Ceftazidime 1.0-128 16 128 Gentamicin 2.0-32 16 32 Continued on following page VOL. 27, 1985 IN VITRO ACTIVITIES OF CEFPIRAMIDE AND APALCILLIN 787

TABLE 1-Continued Organism (no. of isolates) Antibiotic MIC range MiC)0 (pMmi Viridans group streptococci Cefpiramide 0.25-2 0.5 2 (penicillin susceptible) (10) Apalcillin .0.06-0.5 0.25 0.25 Piperacillin s0.06-0.5 0.25 0.5 Aztreonam 128->128 >128 >128 Cefoperazone 0.125-1 0.5 1 Ceftriaxone .0.06-0.5 0.125 0.5 Ceftazidime s0.06-32 2 16 Gentamicin 0.25-4 0.5 2 Viridans group streptococci Cefpiramide 8.0-32 8 32 (penicillin resistant) (10) Apaicillin 2.0-8 4 8 Piperacillin 4.0-32 16 16 Aztreonam >128 >128 >128 Cefoperazone 4.0-16 8 16 Ceftriaxone 1.0-4 2 4 Ceftazidime 16-64 16 32 Gentamicin 2.0-16 8 16 Group G streptococci (10) Cefpiramide 0.125-0.25 0.125 0.25 Apalcillin 0.125 0.125 0.125 Piperacillin 0.125 0.125 0.125 Aztreonam 64 64 64 Cefoperazone 0.25 0.25 0.25 Ceftriaxone s0.06 s0.06 s0.06 Ceftazidime 0.25 0.25 0.25 Gentamicin 8.0 8 8 Listeria monocytogenes (20) Cefpiramide 0.5-8 4 8 Apalcillin .0.06-2 2 2 Piperacillin 0.5-4 2 4 Aztreonam 64->128 >128 >128 Cefoperazone 1.0-64 32 32 Ceftriaxone 1.0->128 128 >128 Ceftazidime 8.0->128 >128 >128 Gentamicin 0.125-0.5 0.5 0.5

Princeton, N.J.; ceftriaxone, Hoffmann-La Roche Inc., Nut- 32-prong replicating device. Plates were examined for growth ley, N.J.; cefoperazone, Pfizer Inc., Groton, Conn.; carben- after 18 h of incubation at 37°C. A single colony or faint haze icillin, Beecham Laboratories, Bristol, Tenn.; ceftazidime, was ignored when determining endpoints. C. jejuni strains Glaxo Laboratories, Fort Lauderdale, Fla.; cefsulodin, were incubated in a microaerophilic atmosphere (Campy Abbott Laboratories, North Chicago, Ill.; and gentamicin, Schering Corp., Kenilworth, N.J. Antibiotic solutions were prepared daily as needed, and antibiotic-containing plates TABLE 2. Number of strains showing synergy, were inoculated within 18 h of indifference, and preparation. antagonism for combinations of agents tested against gram- Susceptibility studies. MICs were determined by an agar negative bacilli dilution technique (16) with Mueller-Hinton agar (BBL Mi- No. of strains showing synergy/indifference/ crobiology Systems, Cockeysville, Md.). The concentration Antibiotic antagonisma of agar was increased to 4% with Bacto-Agar (Difco Labo- combination ratories, Detroit, Mich.) when testing Proteus sp. to prevent K. pneumoniae E. cloacae P. aeruginosa swarming. When streptococci were tested, Mueller-Hinton Cefpiramide and 6/4/0 5/5/0 8/2/0 agar was supplemented with 5% sheep blood. Campylobac- gentamicin terjejuni was tested with brucella agar (BBL) supplemented Apalcillin and 0/10/0 6/4/0 10/0/0 with 10% sheep blood. For Haemophilus influenzae and N. gentamicin gonorrhoeae, chocolate agar supplemented with 1% IsoVi- Cefpiramide and 0/10/0 0/0/10 0/2/8 taleX (BBL) was used. cultures of test cefoxitin Overnight organisms Apalcillin and 0/10/0 0/2/8 0/1/9 in Mueller-Hinton broth (BBL), Todd-Hewitt broth (for cefoxitin streptococci; BBL), or thioglycolate medium (for C. jejuni; Piperacillin and 0/10/0 0/2/8 0/0/10 GIBCO Diagnostics, Madison, Wis.) were diluted in fresh cefoxitin broth to approximately 107CFU/ml. For H. influenzae and Cefpiramide and 0/10/0 0/10/0 1/9/0 N. gonorrhoeae, fresh colonies from chocolate agar plates piperacillin were dispersed in broth to the same density of organisms. Apalcillin and 0/10/0 3/7/0 2/8/0 For Streptococcus pneumoniae, fresh colonies from brucella piperacillin agar plates were dispersed in broth to the same density. a Numerals separated by shills represent the number of strains showing Inocula of approximately 104 CFU were applied with a synergy, indifference, and antagonism, respectively. 788 ALLAN ET AL. ANTIMICROB. AGENTS CHEMOTHER.

TABLE 3. Comparative in vitro activities of antibiotics against resistant organisms Bacteria (no. of isolates) Antibiotic MIC range (MgICml) MICl) Escherichia coli resistant to gentamicin, Cefpiramide 0.5->128 4 32 tobramycin, and amikacin (15) Apalcillin 0.5->128 2 128 Carbenicillin 2.0->256 32 >256 Piperacillin 1.0->128 4 128 Cefoperazone -0.06-32 0.25 32 Moxalactam <0.06-128 0.25 0.5 Aztreonam <0.06->128 0.125 2 Ceftriaxone <0.06->128 0.06 1 Ceftazidime <0.06->128 0.25 8 Pseudomonas aeruginosa resistant to gentamicin, Cefpiramide 2.0->128 8 >128 tobramycin, and amikacin (15) Apalcillin 2.0->128 4 128 Carbenicillin 32->256 128 >256 Piperacillin 4.0->128 16 >128 Cefoperazone 4.0->128 16 >128 Moxalactam 0.25->128 32 >128 Aztreonam 4.0->128 8 >128 Ceftriaxone 2.0->128 128 >128 Ceftazidime 0.25->128 2 64 Serratia marcescens resistant to first- and Cefpiramide 32->128 64 >128 second-generation cephalosporins (10) Apalcillin 8.0->128 32 64 Carbenicillin 16->256 64 256 Piperacillin 4.0->128 4 16 Cefoperazone 2.0->128 4 32 Moxalactam 0.25-64 1 8 Aztreonam 0.125-8 0.25 2 Ceftriaxone 0.25-64 0.5 4 Ceftazidime 0.25-16 0.5 2 Imipenem 0.5-2 1 2 Gentamicin 1.0-32 1 16 Escherichia coli resistant to ampicillin, carbenicillin, Cefpiramide 8.0-128 64 128 and cephalothin (8) Apalcillin 16->128 >128 >128 Piperacillin 16->128 >128 >128 Cefamandole 4.0-32 8 32 Cefoxitin 4.0-32 4 8 Cefoperazone 1.0-32 8 16 Moxalactam 0.125-0.5 0.125 0.25 Aztreonam _0.06-4 0.125 0.125 Ceftriaxone _0.06-1 _0.06 s0.06 Ceftazidime 0.125-8 0.25 0.25 Imipenem 0.25-0.5 0.25 0.25 Gentamicin 0.25-2 1 2 Klebsiella pnteumonia resistant to carbenicillin Cefpiramide 16.0->128 32 >128 and cephalothin (9) Apalcillin 4.0->128 16 >128 Piperacillin 4.0->128 32 >128 Cefamandole 1.0-128 16 128 Cefoxitin 4.0->128 16 64 Cefoperazone 0.25-32 4 32 Moxalactam 0.125-8 0.125 1 Aztreonam _0.06-0.5 0.25 0.25 Ceftriaxone 0.06-0.5 0.125 0.25 Ceftazidime 0.125-4 1 2 Imipenem 0.125-1 0.25 0.5 Gentamicin 0.5-32 2 32

Enterobacter cloacae resistant to Cefpiramide 16->128 >128 >128 carbenicillin and cefamandole (9) Apalcillin 4.0->128 64 >128 Piperacillin 4.0->128 64 >128 Cefoperazone 2.0->128 32 128 Moxalactam 0.125-32 16 16 Aztreonam 0.25-64 16 32 Ceftriaxone 0.25-128 32 128 Ceftazidime 1.0-128 32 128 Imipenem 0.5-2 0.5 1 Gentamicin 0.5-1 0.5 1 Continued on following page VOL. 27, 1985 IN VITRO ACTIVITIES OF CEFPIRAMIDE AND APALCILLIN 789

TABLE 3-Continued MIC range MIC50 MICgo Bacteria (no. of isolates) Antibiotic (p,g/mi) (pug/ml) (,ug/ml) Pseudomonas aeruginosa resistant to Cefpiramide 4.0->128 16 64 carbenicillin (8) Apalcillin 4.0->128 16 64 Piperacillin 16.0->128 32 128 Cefoperazone 16.0->128 32 128 Moxalactam 8.0->128 64 128 Aztreonam 8.0->128 16 >128 Ceftriaxone 8.0->128 64 >128 Ceftazidime 2.0-> 128 4 16 Imipenem 4.0->128 4 >128 Gentamicin 4.0->128 4 128

Pak II; BBL), and N. gonorrhoeae strains were incubated in ters, the activity of apalcillin either equaled or exceeded 5% CO2. All other strains were incubated in room air. those of both piperacillin and mezlocillin (data for mezlocil- Antibiotic combinations were tested in a checkerboard lin not shown). Strains of H. influenzae that produced agar dilution matrix. Synergism was said to be present when P-lactamase were resistant to all three penicillins; against the MIC of each drug tested in combination was fourfold or P-lactamase-negative strains, apalcillin was slightly less ac- more lower than the MIC of each drug tested individually. tive than either piperacillin or mezlocillin. The activity of Antagonism of drug A by drug B was said to be present when apalcillin against members of the Enterobacteriaceae was the MIC of drug A was fourfold or more higher in the comparable to those of the other penicillins. Although it was presence of B than in its absence. Indifference was said to be the most active of the three penicillins tested against L. present when the criteria for neither synergism nor antago- monocytogenes (MIC90 = 2.0 ,ug/ml), against other gram- nism were met. positive organisms, apalcillin was comparable to piperacillin and only slightly less active than mezlocillin (data not RESULTS shown). Apalcillin exhibited poor activity against 24 strains Susceptibility studies. Results of agar dilution susceptibil- of C. jejuni, with an MIC50 of 32 j,g/ml and an MIC9o of 128 ity studies are shown in Table 1. Except for ceftazidime, jig/ml (MIC range, 1.0 to 128.0 jig/ml). Against three strains cefpiramide was the most active cephalosporin tested against of Y. enterocolitica, the range of MICs obtained for apalcil- P. aeruginosa. Against other nonfermenters, its activity was lin was 8 to 16 jig/ml, higher than those obtained for any generally comparable to that of cefoperazone. However, other antibiotic in this study with the exception of cefpir- against most members of the Enterobacteriaceae, cefpiramide. amide was less active than the other cephalosporins tested. Antibiotic combinations. The results of testing these anti- Against gram-positive organisms, the pattern of activity of biotics in combination with other agents are presented in cefpiramide was very similar to that of cefoperazone, and Table 2. The combination of cefpiramide and gentamicin against Listeria monocytogenes it was the most active synergistically inhibited 80% of P. aeruginosa strains, 50% cephalosporin tested (MIC for 90% of the strains tested of Enterobacter cloacae strains, and 60% of Klebsiella [MIC90] = 8 ,ug/ml). C. jejuni strains were resistant to pneumoniae strains tested. Similarly, the combination of cefpiramide, with MICs of .128 ,ug/ml for all of the 24 apalcillin and gentamicin synergistically inhibited 100% of P. strains tested. When cefpiramide was tested against three aeruginosa and 60% of E. cloacae strains tested but none of strains of Yersinia enterocolitica, the MICs obtained ranged the K. pneumoniae strains tested. However, cefoxitin antag- from 8.0 to 32.0 ,ug/ml, higher than those obtained for any onized the activity of cefpiramide against 100% of E. cloacae other antibiotic in this study. and 80% of P. aeruginosa strains. Similarly, cefoxitin antag- Apalcillin was the most active penicillin tested against P. onized the activity of apalcillin against 80% of E. cloacae aeruginosa, with activity equal to that of ceftazidime against and 90% of P. aeruginosa strains tested. Neither cefpir- these isolates (MIC90 = 8 ,ug/ml). Against other nonfermen- amide nor apalcillin antagonized the activity of any other

TABLE 4. Antimicrobial susceptibility of plasmid-containing strains of P. aeruginosa PU21 P-Lactamase MIC (,ug/ml) of: type Cefpiramide Apalcillin Piperacillin Cefoperazone Ceftazidime Imipenem None 4 2 16 16 2 4 TEM-1 64 >128 >128 128 4 4 TEM-2 128 >128 >128 128 2 4 OXA-1 32 128 >128 16 2 4 OXA-2 64 >128 >128 64 8 4 OXA-3 >128 >128 >128 >128 16 4 PSE-1 32 128 >128 64 2 4 PSE-2 128 128 >128 >128 2 4 PSE-3 8 64 128 32 2 4 PSE-4 32 >128 >128 128 2 4 790 ALLAN ET AL. ANTIMICROB. AGENTS CHEMOTHER. drug with which it was combined against any of these strains these agents would appear warranted to determine whether (Table 2). their in vitro activities, particularly against P. aeruginosa, Activity against resistant isolates. The results of suscepti- and their pharmacokinetic properties can be translated into bility testing against selected strains of gram-negative bacilli effective therapy for specific infections. resistant to multiple antibiotics are presented in Table 3. When tested against members of the Enterobacteriaceae LITERATURE CITED resistant to other ,-lactam agents, apalcillin and cefpiramide 1. Barry, A. L., R. N. Jones, L. W. Ayers, T. L. Gavan, E. H. were significantly less active than moxalactam, ceftazidime, Gerlach, and H. M. Sommers. 1984. In vitro activity of apalcillin ceftriaxone, aztreonam, and imipenem. However, against compared with those of piperacillin and carbenicillin against carbenicillin-resistant strains of P. aeruginosa, both apalcil- 6,797 bacterial isolates from four separate medical centers. lin and cefpiramide were slightly more active than the other Antimicrob. Agents Chemother. 25:669-671. agents tested, with the exception of ceftazidime. 2. Calderwood, S. B., A. Gardella, A. M. Philippon, G. A. Jacoby, In otherwise isogenic strains of P. aeruginosa, the pres- and R. C. Moellering, Jr. 1982. Effects of azlocillin in combination with clavulanic acid, sulbactam, and N-formimidoyl thien- ence of any one of nine plasmid-mediated ,-lactamases amycin against P-lactamase-producing, carbenicillin-resistant adversely affected the activities of both cefpiramide and Pseudomonas aeruginosa. Antimicrob. Agents Chemother. apalcillin (Table 4). 22:266-271. 3. Eliopoulos, G. M., A. Gardella, and R. C. Moellering, Jr. 1982. DISCUSSION In-vitro activity of Sch 29482 in comparison with other oral agents. J. Antimicrob. Chemother. 9(Suppl. C):143-152. This study demonstrated the marked activity of both 4. Farber, B. F., G. M. Eliopoulos, J. I. Ward, K. L. Ruoff, V. cefpiramide and apalcillin against P. aeruginosa. The activ- Syriopoulou, and R. C. Moellering, Jr. 1983. Multiply resistant ities of these two agents in this regard are comparable to viridans streptococci: susceptibility to 3-lactam antibiotics and those of the most active of the currently available P-lactams. comparison of penicillin-binding protein patterns. Antimicrob. Against a broad range of other gram-negative and gram-pos- Agents Chemother. 24:702-705. 5. Fass, R. J., and V. L. Helsel. 1984. Comparative in vitro itive organisms, the activities of cefpiramide and apalcillin activities of apalcillin and piperacillin against gram-negative were sufficient to be clinically useful. However, against bacilli. Antimicrob. Agents Chemother. 26:660-664. members of the Enterobacteriaceae, cefpiramide was the 6. Fukusawa, M., H. Noguchi, T. Okuda, T. Komatsu, and K. least active cephalosporin tested. The in vitro susceptibility Yano. 1983. In vitro antibacterial activity of SM-1652, a new results obtained in this study for both agents are in general broad-spectrum cephalosporin with antipseudomonal activity. agreement with those obtained by other investigators (5, 6, Antimicrob. Agents Chemother. 23:195-200. 8, 12-14). 7. Gootz, T. D., C. C. Sanders, and R. V. Goering. 1982. Resist- Against strains selected for multiple resistance, neither ance to cefamandole: derepression of P-lactamases by cefoxitin cefpiramide nor apalcillin appeared to offer a significant and mutation in Enterobacter cloacae. J. Infect. Dis. 146:34-42. 8. Kato, M., M. Inoue, and S. Mitsuhashi. 1982. Antibacterial advantage over other currently available agents. Similarly, activities of SM-1652 compared with those of other broad-spec- when tested against a series of otherwise isogenic strains of trum cephalosporins. Antimicrob. Agents Chemother. P. aeruginosa, the activities of both cefpiramide and apalcil- 22:721-727. lin were markedly reduced in the presence of each of nine 9. Lode, H., A. Elvers, P. Koeppe, and K. Borner. 1984. Compar- different plasmid-mediated P-lactamases, although the activ- ative pharmacokinetics of apalcillin and piperacillin. Antimi- ity of cefpiramide was less affected than that of apalcillin. crob. Agents Chemother. 25:105-108. This is consistent with previous work demonstrating suscep- 10. Nakagawa, K., M. Koyama, H. Matsui, C. Ikeda, K. Yano, N. tibility of both apalcillin and cefpiramide to hydrolysis by a Nakatsuru, K. Yoshinaga, and T. Noguchi. 1984. Pharmacoki- netics of cefpiramide (SM-1652) in humans. Antimicrob. Agents number of 1-lactamases (8, 12). Chemother. 25:221-225. Cefoxitin antagonized the activities of both cefpiramide 11. National Committee for Clinical Laboratory Standards. 1979. and apalcillin against most strains of E. cloacae and P. Approved standard M2-A2 with supplements. Performance aeruginosa. This suggests that induction of the chromosomal standards for antimicrobic disc susceptibility tests, 2nd ed. P-lactamase that nearly all strains of E. cloacae, P. aerugi- National Committee for Clinical Laboratory Standards, Vil- nosa, and many other species of gram-negative bacilli pos- lanova, Pa. sess adversely affects the activities of cefpiramide and 12. Neu, H. C., and P. Labthavikul. 1982. In vitro activity of apalcillin (7, 15). In light of this, it might be anticipated that apalcillin compared with that of other new penicillins and resistance to both of these antibiotics may emerge while anti-Pseudomonas cephalosporins. Antimicrob. Agents Chemo- when ther. 21:906-911. patients are undergoing antibiotic therapy, particularly 13. Noguchi, H., Y. Eda, H. Tobiki, T. Nakagome, and T. Komatsu. P. aeruginosa or E. cloacae is the infecting species. This is 1976. PC-904, a novel broad-spectrum semisynthetic penicillin a potential problem that cefpiramide and apalcillin share with marked antipseudomonal activity: microbiological evalua- with many other P-lactam antibiotics (15). tion. Antimicrob. Agents Chemother. 9:262-273. Based on these in vitro results, a major potential applica- 14. Pfaller, M. A., A. C. Niles, and P. R. Murray. 1984. In vitro tion of these two new drugs would be in the treatment of antibacterial activity of cefpiramide. Antimicrob. Agents Che- infections due to P. aeruginosa. In addition, both agents mother. 25:368-372. have potential pharmacokinetic advantages. Cefpiramide 15. Sanders, C. C., and W. E. Sanders, Jr. 1983. Emergence of has the longest half-life of any of the tested (10) resistance during therapy with the newer P-lactam antibiotics: P-lactams role of inducible P-lactamase and implications for the future. with the exception of ceftriaxone, a drug which was much Rev. Infect. Dis. 5:639-648. less active against P. aeruginosa in this study. Apalcillin 16. Washington, J. A., II, and V. L. Sutter. 1980. Dilution suscep- differs from the other extended-spectrum penicillins in that it tibility test: agar and macro-broth dilution procedures, p. is primarily excreted via hepatobiliary mechanisms (9). In 453-458. In E. H. Lennette, A. Balows, W. J. Hausler, Jr., and certain settings, this may be an important consideration. J. P. Truant (ed.), Manual of clinical microbiology, 3rd ed. Given these characteristics, clinical evaluation of both of American Society for Microbiology, Washington, D.C.